The classical amyloid cascade hypothesis of Alzheimer's disease (AD) states that soluble amyloid beta (A) monomers aggregate into fibrillar plaques and lead to hyperphosphorylated tau protein filaments, neurofibrillary tangles, gliosis, neuronal loss and dementia. However, A plaques are not specific to AD, and are seen with other neurodegenerative disorders as well as cognitively normal patients, particularly in the elderly. The causes and clinical significance of A plaque formation in cognitively normal subjects is not fully understood although numerous studies support that increased fibrillar A on PET is a risk factor for future cognitive decline. Sepsis, a severe systemic inflammatory condition, results in short and long term neurocognitive dysfunction. Acutely, sepsis causes mitochondrial dysfunction and oxidative damage. Longer-term brain dysfunction following sepsis is poorly understood. We have shown a transient increase in cytokines and soluble A monomers in the rat brain with experimental sepsis (LPS) but progressive accumulation of A neuritic plaques throughout the interval of observation (7-9 d). Preliminary RNAseq analysis suggests increased levels of transcripts with LPS that may affect formation, stabilization or reduced clearance of neuritic A plaques. We hypothesize that sepsis and other systemic inflammatory conditions result in neuroinflammation, contribute to A neuritic plaque burden and increase the risk of cognitive dysfunction. We proposed to clarify the molecular basis, neurocognitive features, and long-term outcome of sepsis-induced brain dysfunction. Inherent in the success of this goal is the development of non-invasive imaging tools to track acute and chronic neuropathological manifestations of sepsis. The specific aims are: (1) To determine whether A neuritic plaques that accumulate in the rat sepsis model eventually resolve or whether they result in the same downstream neuropathological consequences as occur in AD. This will be compared, spatially and temporally, to evidence for mitochondrial dysfunction and oxidative damage; (2) to define molecular events resulting from experimental sepsis that mediate A plaque formation and neuronal damage based on our preliminary RNAseq data; (3) To perform longitudinal neurocognitive tests in rats to identify cognitive abnormalities resulting from experimental sepsis, and correlate these findings with neuropathology in regions implicated as abnormal; (4) To perform longitudinal studies with and without aggressive immune modulation to determine whether LPS-induced A plaque formation, associated neuropathological lesions, mitochondrial dysfunction and associated neurocognitive abnormalities can be pharmacologically mitigated or reversed; (5) to develop imaging strategies that best identify both acute and chronic brain pathology resulting from experimental sepsis, and correlate changes in these imaging findings with pharmacologic immune modulation (aim 4). These will include advanced microPET and MRI techniques. These imaging measures will be validated by relevant tissue correlates in the brain itself.